Septic shock and severe sepsis represent a major public health problem in the United States, despite the development of increasingly powerful antibiotics and advanced forms of intensive care unit-based support modalities (see, e.g., Shanley, T. et al. Sepsis, 3rd Ed., St. Louis, Mo., Mosby (2006)). Worldwide, septic shock affects millions of adults, killing approximately one in four (see, e.g., Dellinger, R. et al. Crit. Care Med. 36:296-327 (2008)). A recent study suggests that the incidence and the mortality rates of septic shock in adults are increasing in the United States (Dombrovskiy, V. et al. Crit. Care Med. 35:1244-50 (2007)).
Septic shock is also a major problem in the pediatric age group, as there are ˜42,000 cases of pediatric septic shock per year in the United States alone, with a mortality rate of ˜10% (see, e.g., Watson, R. et al. Am. J. Respir. Crit. Care Med. 167:695-701 (2003)). While the pediatric mortality rate is lower than that of adults, it nonetheless translates to more than 4,000 childhood deaths per year and countless years of lost productivity due to death at a young age. While this high number of pediatric deaths per year from septic shock indicates that more children die per year in the United States from septic shock as the primary cause than those children who die from cancer, funding specifically targeted toward pediatric septic shock is substantially lower than that for pediatric cancer.
Heterogeneity is a major feature of pediatric septic shock, including widely variable mortality risk [Hanna W, Wong H R (2013) Pediatric sepsis: challenges and adjunctive therapies. Crit Care Clin 29: 203-222. doi: 10.1016/j.ccc.2012.11.003]. In the absence of tools to accurately assess baseline mortality risk, clinicians have little objective information to benchmark septic shock outcomes, adjust for risk in analyses of clinical data, risk stratify patients for interventional clinical trials, and guide decisions on which patients need the most aggressive treatment, and which do not.
Reliable stratification of outcome risk is therefore fundamental to effective clinical practice and clinical research (Marshall J. Leukoc. Biol. 83:471-82 (2008)). A reliable and widely accepted outcome risk stratification tool specific for septic shock in pediatric patients would be beneficial for stratification for interventional clinical trials, better-informed decision making for individual patients, and as a metric for quality improvement efforts.
A recently published roadmap for future research in the field of sepsis encourages incorporation of biomarkers and enrichment strategies for clinical trials [Cohen et al. Sepsis: a roadmap for future research. Lancet Infect Dis 2015, 15(5):581-614]. Several programs of research are attempting to directly improve clinical care by providing tools to differentiate patients with septic shock on the basis of mortality risk, and on the basis of their clinical phenotype [Knox et al. Phenotypic clusters within sepsis-associated multiple organ dysfunction syndrome. Intensive Care Med 2015, 41(5):814-822; Wong et al. Developing a clinically feasible personalized medicine approach to pediatric septic shock. Am J Respir Crit Care Med 2015, 191(3):309-315; Wong H R, et al. A multibiomarker-based outcome risk stratification model for adult septic shock. Crit Care Med 2014, 42(4):781-789]. While differentiating between septic shock phenotypes might guide selection of treatments specific to the phenotypic characteristics, tools that inform clinicians in real time about mortality risk both within and across septic shock phenotypes can help determine who needs aggressive and potentially higher risk treatments and who does not.
The Pediatric Sepsis Biomarker Risk Model (PERSEVERE) estimates baseline 28-day mortality risk for children with septic shock [Wong et al. The pediatric sepsis biomarker risk model. Crit Care 2012, 16(5):R174; Alder M N, Lindsell C J, Wong H R: The pediatric sepsis biomarker risk model: potential implications for sepsis therapy and biology. Expert Rev Anti Infect Ther 2014, 12(7):809-816]. PERSEVERE is also described in U.S. Pat. No. 9,238,841.
PERSEVERE was derived using Classification and Regression Tree (CART) methodology, and the model incorporates a panel of biomarkers and age. The PERSEVERE biomarkers were selected objectively, using discovery oriented transcriptomic studies [Kaplan J M, Wong H R: Biomarker discovery and development in pediatric critical care medicine. Pediatr Crit Care Med 2011, 12(2):165-173]. PERSEVERE performs well when tested in a heterogeneous septic shock cohort [Wong et al: Testing the prognostic accuracy of the updated pediatric sepsis biomarker risk model. PLoS One 2014, 9(1):e862421, but it is unknown how PERSEVERE performs when applied to distinct clinical phenotypes of septic shock.
Thrombocytopenia-associated multiple organ failure (TAMOF) has been proposed as an important clinical phenotype of septic shock, with high mortality that is potentially modifiable by plasma exchange [Nguyen et al. Intensive plasma exchange increases a disintegrin and metalloprotease with thrombospondin motifs-13 activity and reverses organ dysfunction in children with thrombocytopenia-associated multiple organ failure. Crit Care Med 2008, 36(10):2878-2887; Nguyen et al. Thrombocytopenia-associated multiple organ failure. In: Pediatric Critical Care Medicine: Basic Science and Clinical Practice. Edited by Wheeler D S, Wong H R, Shanley T P, vol. 3. New York: Springer; 2014: 481-492; Nguyen et al. Acquired ADAMTS-13 deficiency in pediatric patients with severe sepsis. Haematologica 2007, 92(1):121-124]. TAMOF is defined by new onset multiple organ failure with new onset thrombocytopenia. The mechanistic link between thrombocytopenia and organ failure is thought to involve a form of microangiopathy analogous to thrombotic thrombocytopenic purpura (TTP), including decreased levels of ADAMTS-13 (A Disintegrin And Metalloprotease with ThromboSpondin motifs) and increased von Willebrand factor activity [Nguyen T C, Carcillo J A: Understanding the role of von Willebrand factor and its cleaving protease ADAM TS13 in the pathophysiology of critical illness. Pediatr Crit Care Med 2007, 8(2):187-189]. ADAMTS-13 regulates microvascular thrombosis by cleaving large and ultra-large thrombogenic von Willebrand factor multimers into smaller, less thrombogenic forms. Preliminary experience suggests plasma exchange restores ADAMTS-13 levels and restores organ function in children with TAMOF, although an appropriately powered study has yet to be conducted.